Researchers Link Structural Protein to Deadly Form of Breast Cancer

Researchers have linked a structural protein called nestin to a particularly deadly form of breast cancer, identifying a new biomarker that could lead to earlier detection and better treatment.

In the January 15 issue of Cancer Research, researchers from Dartmouth Medical School demonstrate that nestin could represent a selective biological marker for basal epithelial breast tumors, a highly aggressive cancer with similarities to mammary stem cells, the regenerative cells believed to be the site of breast cancer initiation.

"Patients with this type of breast cancer are at high risk for recurrence," said James DiRenzo, Ph.D., assistant professor at Dartmouth Medical School. "Ideally, a marker like nestin would enable clinicians to monitor these patients through frequent tests of a biomarker and, in doing so, detect the cancer before it has a chance to come back."

Basal epithelial tumors lack important molecular targets such as the estrogen receptor, progesterone receptor and Her2. This not only makes positive diagnosis difficult, say researchers, but also eliminates several important lines of therapy, such as tamoxifen or Herceptin, that work well for other breast cancer subtypes.

"Currently, there is no direct means of determining if a breast cancer is a basal epithelial tumor - doctors only know for certain once the other forms of breast cancer are ruled out," DiRenzo said. "This type of breast cancer is generally difficult to manage, but several important studies have shown that it is more likely than other breast cancer subtypes to respond to certain types of therapy, which highlights the need for a definitive diagnostic marker."

The basal epithelial breast cancer subtype represents 17 to 37 percent of all breast cancers and is more common in premenopausal African American women than in other demographic groups. Among breast cancers, this subtype is known to have an early age of onset and a very short time between treatment and relapse. It is more commonly detected during normal screening mammogram intervals than other screening subtypes, which likely reflects its aggressive nature. These important clinical correlations likely explain why this subtype disproportionately accounts for breast cancer mortality, according to DiRenzo.

In a retrospective study of breast cancer tumors lacking estrogen receptors, progesterone receptors and Her2, DiRenzo and his colleagues found extremely high amounts of nestin in 14 of 16 tumor samples examined. While the researchers plan to strengthen their findings with a larger prospective study, their results offer a crucial first step in diagnosis and management of a disease that is notoriously difficult to control. Consistent with other studies showing that breast cancers associated with inherited mutations in BRCA1 display the basal phenotype, DiRenzo and colleagues found high levels of nestin in these tumors as well.

Nestin is a long filamentous protein found in adult stem cells in the central nervous system. While scientists do not know its exact function, the protein is thought to have a role in stabilizing the structure of adult stem cells as they regenerate and divide into daughter cells.

"Normal basal epithelial tissue produces nestin, but basal epithelial tumors produce a tremendous amount of nestin, which likely represents an abnormal expansion of the basal epithelia." DiRenzo said. "If it is indeed specific to regenerative cells, then it will make for an excellent diagnostic tool for a cancer of regenerative mammary cells."

According to the DiRenzo, another important next step will be finding an efficient means of detecting nestin in a clinical screening setting. While it seems unlikely that a blood test would be sufficient, DiRenzo believes that a non-invasive test that collects samples from mammary ducts may enable the development of a screening tool for at-risk patients.

The study was funded by the National Cancer Institute, the U.S. Department of Defense Breast Cancer Research Program and the Mary Kay Ash Charitable Foundation.